Li et al.

Journal of Cardiothoracic Surgery (2020) 15:40

https://doi.org/10.1186/s13019-020-1084-7

RESEARCH ARTICLE Open Access

Comparison of different bridging

anticoagulation therapies used after
mechanical heart valve replacement in
Chinese patients - a prospective cohort
study
Bo-Xia Li1†, Shi-Dong Liu2,3†, Liang Qi3, Shusen Sun4, Wei Sun3, Yuan-Min Li3, Bing Song3* and Xin-An Wu1*

Abstract
Objective: To assess different bridging anticoagulation therapies early after mechanical heart valve replacement
(MHVR) in Chinese patients.
Methods: We performed a prospective, single-center, observational cohort study of 305 patients who underwent
elective MHVR with different bridging anticoagulation regimens. Patients enrolled in the study were divided into
three bridging therapy groups: the unfractionated heparin (UFH) group (n = 109), the low-molecular-weight heparin
(LMWH) group (n = 97), and the UFH with sequential LMWH (UFH-LMWH) group (n = 99). All patients were followed
for 4 weeks.
Results: Two patients experienced thromboembolic stroke events in the UFH group. The LMWH group was
associated with an increase in the incidence of bleeding events compared with the UFH group (10.3% VS 2.8%; P =
0.03). With a comparison of LMWH and UFH group in secondary endpoints, the statistical test for significance
indicated a trend of reduced ICU length of stay (P = 0.08), postoperative length of stay (P = 0.08) and time of
achieving target INR (P = 0.06). The creatinine level (odds ratio = 1.03; 95% confidence interval = 1.01 to 1.05; P =
0.02) and hypertension (odds ratio = 3.72; 95% confidence interval = 1.35 to 10.28; P = 0.01) were risk factors for
bleeding events.
Conclusion: For Chinese patients, the LMWH bridging anticoagulation presents the increased the incidence of
bleeding events, but enables patients to benefit from achieving an early anticoagulation effect. Close follow-up and
personalized management are required in patients with thromboembolic and bleeding risk factors.
Trial registration: Chinese Clinical Trial Registry ChiCTR1800019841. Registered 2 December 2018 retrospectively.
Keywords: Bridging anticoagulation, Mechanical heart valve replacement, Low-molecular-weight heparin, Chinese
patients

* Correspondence: songbinldyy@163.com; xinanwu6511@163.com

†
Bo-Xia Li and Shi-Dong Liu contributed equally to this work.
3
Cardiovascular Surgery, First Hospital of Lanzhou University, Lanzhou
730000, China
1
Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou
730000, China
Full list of author information is available at the end of the article

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40
Introduction
Bridging anticoagulation after mechanical heart valve re-
placement (MHVR) has been accepted as a standard of
practice in cardiac surgery centers worldwide. However,
how to manage bridging anticoagulation regimens re-
mains a challenge with no existing accordance [1]. The
American College of Chest Physician (ACCP) guidelines
recommend the use of low-dose unfractionated heparin
(UFH), low-dose low-molecular-weight heparin
(LMWH) or therapeutic dose LMWH over therapeutic
dose of UFH in 2012 [2]. Bridging anticoagulation with
either intravenous UFH or subcutaneous LMWH is rec-
ommended in the 2014 American College of Cardiology/
American Heart Association (ACC/AHA) guidelines.
When LMWH is used, therapeutic weight-adjusted
doses are given twice daily. The use of bridging heparin
after surgery must be individualized, depending on the
risks of bleeding and thrombosis [3]. The 2017 ESC/
EACTS Guidelines for the Management of Valvar Heart
Disease show that intravenous UFH monitored to an ac-
tivated partial thromboplastin time (APTT) of 1.5–2.0
times the control value, enables rapid anticoagulation to
be obtained before international normalized ratio (INR)
rises [4]. Lack of accordance among the guidelines may
generate a broad standard of practice in cardiovascular
centers in bridging anticoagulation after MHVR [5].
The use of different bridging anticoagulation therapies
after MHVR remains under discussion because of the
risk of bleeding and thromboembolic events postopera-
tively [6]. Additionally, the doses of bridging anticoagu-
lants and the target range of bridging anticoagulation
are significantly different between Chinese cardiac sur-
gery centers and foreign centers [7, 8]. At present, there
is no clear Chinese guideline or consensus on bridging
anticoagulation after MHVR, and few clinical studies
have been conducted in Chinese patients [7–12].
We performed a prospective, single-center, observa-
tional cohort study to evaluate the efficacy and safety of
different bridging anticoagulant regimens following early
MHVR, and aim to provide Chinese evidence for the de-
velopment of international guidelines.
Patients and methods
Study patients
From January 1, 2016, to December 1, 2018, 352 patients
who underwent elective MHVR in the First Hospital of
Lanzhou University were registered in the clinical trial
before the surgery. The inclusion criteria were patient’s
age ≥ 18 years and had MHVR surgery. The exclusion
criteria were pregnancy, dialysis, aortic dissection, crit-
ical perioperative state, recent neurologic event and se-
vere renal insufficiency (serum creatinine >150 μmol/L)
before operation; bioprosthetic heart valve replacement,
severe renal insufficiency (serum creatinine > 150 μmol/
Page 2 of 10
L), intra-aortic balloon counterpulsation, duration of in-
tubation more than 48 h and patients who were adminis-
tered LMWH for less than 2 days after surgery.
Informed consent was obtained from all participants in-
cluded in the study. The study was approved by the eth-
ics committee of the First Hospital of Lanzhou
University (LDYYLL2018–154).
Study design
Patients who met the inclusion and exclusion criteria
were recruited consecutively in the prospective, single-
center, observational cohort study. The study was regis-
tered at the Chinese Clinical Trial Registry, registration
number ChiCTR1800019841. During a surgical proced-
ure, UFH was given to sustain an activated clotting time
above 400 s. When the cardiopulmonary blood bypass
was stopped, protamine sulfate was used to neutralize
UFH anticoagulation. At the end of the surgery, two sur-
gical drains were placed around the heart, and, if neces-
sary, a third surgical drain was placed in the pleural
cavities. In the early postoperative period, patients stayed
in the ICU ward until they achieved respiratory and
hemodynamic stability; then, they were transferred to
the general ward. The surgical drains were removed
when the drainage volume was less than 50 ml/d in the
general ward.
Bridging anticoagulation was initiated at 6 h postoper-
atively either subcutaneous UFH 25 IU/kg/dose four
times daily or subcutaneous LMWH 4000 IU of anti-Xa/
dose twice daily. Warfarin, starting dose 3 mg, was given
as soon as patients were extubated on the postoperative
day 1 or 2. Bridging anticoagulants were given until INR
was within the target range for 2 consecutive days (1.5
to 2.5 for aortic valve replacement, 1.8 to 3.0 for mitral
valve replacement and bivalve replacement, 2.5 to 3.0 for
tricuspid valve replacement) [13, 14].
According to the physicians’ orders after surgery, pa-
tients enrolled in the study were divided into three
groups: the UFH group, the UFH-LMWH group and the
LMWH group. Regardless of ICU or general ward stays,
UFH was used as a monotherapy in the UFH group, and
LMWH was used as a monotherapy in the LMWH
group. For patients in the UFH-LMWH group, UFH was
used as monotherapy in the ICU, and it was replaced by
LMWH in the general ward to bridge anticoagulation
(Fig. 1). All patients were followed for 4 weeks after
operation.
Endpoints
The primary endpoint was the occurrence of thrombo-
embolic or bleeding events during the 4-week follow-up.
Thromboembolic events included transient stroke, per-
manent stroke, peripheral embolism, and valve throm-
bosis. Bleeding events included proved fatal bleeding,
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40
Fig. 1 Study Flowchart
intracranial hemorrhage, retroperitoneal bleeding, re-
quiring an intervention, transfusion of ≥2 U of red blood
cells, resulting in chronic sequelae or prolongation of
the hospital stay, epistaxis, airway bleeding, hematuria,
hematemesis, gastrointestinal bleeding, and subcutane-
ous hemorrhage. The secondary endpoints included a
volume of drainage, ICU length of stay, postoperative
length of stay, and time of achieving target INR. The
third endpoints were costs, including hospital costs,
medicine costs and the drug share (ratio of medicine
costs over hospital costs).
Statistical analysis
Continuous variables are expressed as mean ± standard
deviation (SD), and categorical variables are expressed as
numbers (percentages). ANOVA adjusted by Bonferro-
ni’s method was used to test for statistical significance in
continuous data, and Chi-square test or Fisher’s exact
test was used to determine statistical significance in cat-
egorical data. A P value of less than 0.05 was considered
Page 3 of 10
to be statistically different. Potential risk factors for
thromboembolic or bleeding events were first tested by
univariate analysis, and the variables tested included:
gender, age, weight, body mass index (BMI), left ven-
tricular ejection fraction (LVEF), CHA2DS2-VASc-
Score, the New York Heart Association functional
(NYHA) class, smoking status, hypertension, diabetes,
atrial fibrillation, coronary artery disease, pulmonary
hypertension, infective endocarditis, history of previous
cardiovascular surgery, history of previous embolism,
history of previous bleeding, hemoglobin level, platelet
count, albumin, creatinine level, triglycerides, low dens-
ity lipoprotein (LDL)-C, prothrombin time, fibrinogen
level, operative characteristics, cross-clamp time, total
bypass time, and postoperative bridging anticoagulation
therapies.
Only significant variables with a P value less than 0.15
in the univariate analysis were used in a multivariable lo-
gistic regression analysis (with a forward, stepwise
method based on the likelihood ratio test). The odds
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40
ratios and their corresponding 95% confidence intervals
were showed in addition to their associated 2-sided P-
values. All date were calculated and analyzed using Soft-
ware Package for Statistics and Simulation (IBM SPSS
version 22.0, IBM Corp Armonk, NY).
Results
Patient demographics and baseline characteristics
A totally of 352 patients who underwent elective MHVR
were registered in the clinical trial before the surgery.
Within this population, 305 patients (86.6%) met the in-
clusion and exclusion criteria, and received postoperative
different bridging anticoagulation regimens. Thirty-one
patients and 16 patients were excluded from cohort due
to the preoperative and postoperative exclusion criteria,
respectively. According to the postoperative physicians’
orders, patients enrolled in the study were divided into
three bridging therapy groups: the UFH group (n = 109),
the UFH-LMWH group (n = 99) and the LMWH group
(n = 97). The patient demographics and baseline charac-
teristics are shown in Table 1. Despite the lack of
randomization, the three groups were well balanced for
the patient demographics and baseline characteristics.
Primary endpoints
2(1.8%) patients who underwent MVRs experienced
thromboembolic events at postoperative day 6 and 16,
respectively, in the UFH group (Table 2). 1(0.9%) patient
occurred permanent stroke at INR 1.77 during bridging
anticoagulation; another 1(0.9%) patient occurred transi-
ent stroke at INR 2.15 during warfarin therapy alone. In
the UFH-LMWH group and the LMWH group, none of
the patients experienced thromboembolic event. The
trial did not have enough thromboembolic events to
provide evidence of treatment efficacy.
Bleeding events during 4 weeks of follow-up occurred
in 3(2.8%) of patients in the UFH group, 5(5.1%) of pa-
tients in the UFH-LMWH group and 10(10.3%) of pa-
tients in the LMWH group (Table 3). These values
represent a relative increase of 2.7 times in bleeding
events with the LMWH group as compared with the
UFH group (P = 0.03), indicating statistical significance.
A relative increase of 82% in bleeding events in the
UFH-LMWH group as compared with the UFH group
(P = 0.39), and a relative increase of one time in bleeding
events with the LMWH group as compared with the
UFH-LMWH group (P = 0.16), both not meeting the cri-
teria with statistical differences (Fig. 2).
All bleeding events were minor bleeding events, as de-
fined by International Society of Thrombosis and
Haemostasis (ISTH). The INRs were above the target
range in 4(22.2%) and the INRs of other 14(77.8%) were
below or within the target range, all of whom presented
with a bleeding event (Table 2). Within the period of
Page 4 of 10
bridging anticoagulation, 2(1.8%) patients in the UFH
group, 3(3.0%) patients in the UFH-LMWH group,
5(5.2%) patients in the LMWH group occurred bleeding
events, but no statistical difference was found among the
three groups (Table 3).
The secondary endpoints
With a comparison of LMWH and UFH group in sec-
ondary endpoints, volume of drainage 4 days after sur-
gery, ICU length of stay (3.7 ± 0.8 VS 4.2 ± 2.5; P = 0.08),
postoperative length of stay (14.6 ± 4.1 VS 15.8 ± 4.2;
P = 0.08), and time of achieving target INR (10.0 ± 2.2
VS 10.9 ± 2.8; P = 0.06) were not statistically different.
The secondary endpoints had no statistical differences
with the UFH-LMWH group as compared with the UFH
group in volume of drainage 4 days after surgery, ICU
length of stay, postoperative length of stay and time of
achieving target INR (Table 3). Similarly compared with
the UFH-LMWH group, the LMWH group also had no
statistical differences in secondary endpoints (Fig. 3).
The third endpoints
There were no statistically differences in hospital costs,
medicine costs and the drug share among the three
groups (Table 3).
Analysis of risk factors for bleeding
The trial did not have enough thromboembolic events to
use a multivariable logistic regression analysis. Risk fac-
tors for bleeding events identified by univariate analysis
were: male gender (56.8% VS 77.8% in control and
bleeding event groups, respectively; P = 0.13); weight
(63.4 ± 9.9 kg VS 67.7 ± 11.4 kg in control and bleeding
event groups, respectively; P = 0.08); CHA2DS2-VASc
score (1.56 ± 0.94 VS 1.94 ± 0.87 in control and bleeding
event groups, respectively; P = 0.09); the New York Heart
Association class III or greater (66.6% VS 88.9% in con-
trol and bleeding event groups, respectively; P = 0.09),
hypertension (14.6% VS 38.9% in control and bleeding
event groups, respectively; P = 0.01), creatinine level
(73.7 ± 15.6 μmol/L VS 83.0 ± 22.8 μmol/L in control and
bleeding event groups, respectively; P = 0.11); and post-
operative bridging anticoagulation therapy (P = 0.07).
The multivariable logistic regression analysis revealed
that the creatinine level (odds ratio = 1.03; 95% confi-
dence interval = 1.01 to 1.05; P = 0.02) and hypertension
(odds ratio = 3.72; 95% confidence interval = 1.35 to
10.28; P = 0.01) were risk factors for bleeding events
(Fig. 4).
Discussion
Our prospective, single-center, observational cohort
study demonstrated that using LMWH monotherapy in-
creased the incidence of bleeding events after elective
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40 Page 5 of 10

Table 1 Baseline Characteristics of Patients

Characteristic the UFH group (n = 109) the UFH-LMWH group (n = 99) the LMWH group (n = 97) P Value
Male, n (%) 63 (57.8%) 63 (63.6%) 51 (52.6%) 0.29
Age, years 50.3 ± 10.6 49.7 ± 11.1 52.4 ± 10.2 0.19
Weight, kg 63.1 ± 9.8 63.5 ± 10.3 64.4 ± 10.0 0.66
BMI, kg/m2 a 22.6 ± 3.0 22.3 ± 3.2 23.1 ± 2.7 0.17
LVEF, % 57.1 ± 5.8 55.7 ± 7.0 56.3 ± 6.4 0.23
CHA2DS2-VASc-Score 1.5 ± 0.9 1.5 ± 0.9 1.7 ± 1.0 0.12
b
NYHA class III or IV, n (%) 75 (68.8%) 65 (65.7%) 67 (69.1%) 0.85
Current smoker, n (%) 21 (19.3%) 24 (24.2%) 20 (20.6%) 0.67
Hypertension, n (%) 13 (11.9%) 16 (16.2%) 20 (20.6%) 0.24
Diabetes, n (%) 2 (1.8%) 3 (3.0%) 2 (2.1%) 0.83
c
Atrial fibrillation, n (%) 34 (31.2%) 23 (28.9%) 32 (33.0%) 0.27
Coronary artery disease, n (%) 5 (4.6%) 8 (8.1%) 10 (10.3%) 0.29
Pulmonary hypertension, n (%) 17 (15.6%) 17 (17.2%) 15 (15.5%) 0.94
Infective endocarditis, n (%) 4 (3.7%) 4 (4.0%) 2 (2.1%) 0.71
History of aspirin, n (%) 4 (3.7%) 7 (7.1%) 8 (8.2%) 0.36
Previous cardiovascular surgery, n (%) 0 (0.0%) 1 (1.0%) 0 (0.0%) 0.35
Previous embolism, n (%) 5 (4.6%) 3 (3.0%) 4 (4.1%) 0.84
Previous bleeding, n (%) 3 (2.8%) 5 (5.1%) 3 (3.1%) 0.64
Biologic data
Hemoglobin, g/L 143.2 ± 19.7 145.6 ± 23.0 141.1 ± 18.7 0.32
9
Platelet count, 10 /L 173.5 ± 69.0 171.4 ± 51.3 180.1 ± 66.0 0.60
Albumin, g/L 42.9 ± 3.7 42.4 ± 3.8 43.3 ± 3.2 0.20
Creatinine, μmol/L 71.4 ± 11.2 75.1 ± 20.7 76.7 ± 15.5 0.06
Triglycerides, mmol/L 1.2 ± 0.6 1.4 ± 0.9 1.3 ± 0.6 0.41
d
LDL-C, mmol/L 2.5 ± 0.8 2.6 ± 0.9 2.6 ± 0.9 0.82
Prothrombin time, sec 12.7 ± 3.8 12.5 ± 3.5 12.4 ± 2.8 0.34
Fibrinogen, g/L 3.0 ± 0.8 2.9 ± 0.8 3.0 ± 0.9 0.76
Operative Characteristics
AVR e 33 (30.3%) 33 (33.3%) 29 (29.9%) 0.85
MVR f 37 (33.9%) 25 (25.3%) 32 (33.0%) 0.34
g
BVR 22 (20.2%) 20 (20.2%) 21 (21.6%) 0.96
Bentall h 17 (15.6%) 21 (21.2%) 15 (15.5%) 0.47
Cross-clamp time, minutes 82.8 ± 35.1 83.4 ± 36.1 82.6 ± 29.4 0.98
Total bypass time, minutes 121.6 ± 44.0 117.1 ± 43.0 117.0 ± 37.6 0.67
Continuous variables are expressed as mean ± SD; categorical variables are expressed as number (percentage)
a
Body mass index (kg/m2); bNew York Heart Association functional class;
c
Includes transient, persistent, permanent atrial fibrillation; dLow density lipoprotein cholesterin
e
Aortic valve replacement; fMitral valve replacement; gBivalve replacement
h
Aortic valve replacement +ascending aorta replacement

MHVR, but contributed to a significant reduction in
ICU length of stay. Additionally, this study revealed that
the creatinine level and hypertension were risk factors of
bleeding events.
Regarding bridging anticoagulation protocol, subcuta-
neous UFH or LMWH bridging anticoagulant was ad-
ministered 6 h after surgery, and warfarin was
administered postoperative day 1 or 2 after extubation.
Patients’ INRs were reviewed intermittently during
hospitalization, and warfarin doses were adjusted ac-
cording to INRs in order to reach target INRs stably.
When INRs were stable for more than 2 days, UFH and
LMWH were discontinued. The therapeutic range of
INR for aortic or mitral valve replacement differs from
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40 Page 6 of 10

Table 2 Bleeding and Thromboembolic events

a
Endpoints events the UFH group (n = 109) INR the UFH-LMWH group (n = 99) INR the LMWH group (n = 97) INR
Bleeding events 3 (2.3%) 2.67 5 (6.3%) 2.69 10 (10.3%) 2.77
Epistaxis 1 (0.8%) 2.21 3 (3.8%) 2.31 7 (7.3%) 2.42
Airway bleeding 0 (0) – 1 (1.3%) 4.05 b
1 (1.0%) 3.85b
Hematuria 1 (0.8%) 2.38 0 (0) – 1 (1.0%) 2.55
Hematemesis 0 (0) – 1 (1.3%) 2.46 0 (0) –
Gastrointestinal bleeding 1 (0.8%) 3.42b 0 (0) – 1 (1.0%) 4.37b
Thromboembolic events 2 (1.6%) 1.96 0 (0) – 0 (0) –
Permanent stroke 1 (0.8%) 1.77 0 (0) – 0 (0) –
Transient stroke 1 (0.8%) 2.15 0 (0) – 0 (0) –
a
The average INR value at the occurrence of the bleeding event
b
The INRs were above the target range of the corresponding MHVR

the values recommended by the European or North
American Societies (EACTS/ESC and AHA/AATS),
however, Haibo Z’s and Dong L’s studies proved that the
relatively low anticoagulant strategy efficiently prevents
thrombosis and hemorrhage complications in the Chin-
ese patients [13.14].
In our prospective, observational cohort study, all pa-
tients enrolled in the study were divided into three
groups according to the postoperative physicians’ orders
without randomization. On the other hand, rigorously
screened and excluded patients based on inclusion and
exclusion criteria. These generated unequal patient
numbers among the three study cohorts. Nevertheless,
the various comorbidities, which might bear an add-
itional risk for thromboembolism or bleeding complica-
tions, were not significantly different among three
groups.
The three study cohorts had comparable CHA2DS2
-VASc score, which provides a way to evaluate the dif-
ference in thromboembolic risk before MHVR. Two

Table 3 Endpoints
Variable the UFH group (n = 109) the UFH-LMWH group (n = 99) P the LMWH group (n = 97) P
value value
Patients Patients Patients
Primary endpoints
All thromboembolic events 2 (1.8%) 0 (0) – 0 (0) –
thromboembolic events a 1 (0.9%) 0 (0) – 0 (0) –
All bleeding events 3 (2.8%) 5 (5.1%) 0.39 10 (10.3%) 0.03
bleeding events b 2 (1.8%) 3 (3.0%) 0.91 5 (5.2%) 0.35
Secondary endpoints
Volume of drainage (ml)
postoperative day 1 296.8 ± 186.2 291.2 ± 170.3 1.00 263.8 ± 175.3 0.55
postoperative day 2 203.5 ± 103.7 188.2 ± 113.2 0.95 187.5 ± 111.6 0.89
postoperative day 3 80.8 ± 66.9 91.5 ± 73.2 0.80 86.5 ± 68.4 1.00
postoperative day 4 40.0 ± 40.3 47.8 ± 49.6 0.68 40.8 ± 49.4 1.00
ICU length of stay (d) 4.2 ± 2.5 4.0 ± 1.4 0.97 3.7 ± 0.8 0.08
Postoperative length of stay (d) 15.8 ± 4.2 15.3 ± 3.5 0.98 14.6 ± 4.1 0.08
Time of achieving target INR (d) 10.9 ± 2.8 10.5 ± 3.2 0.78 10.0 ± 2.2 0.06
Third endpoints
Hospital costs (yuan) 108,884.5 ± 26,641.7 109,900.5 ± 37,380.7 1.00 105,976.4 ± 22,249.5 1.00
Medicine costs (yuan) 41,214.3 ± 14,809.6 41,405.9 ± 13,368.3 1.00 39,176.9 ± 10,788.4 0.81
Medicine costs /Hospital costs 0.37 ± 0.07 0.38 ± 0.07 1.00 0.37 ± 0.07 1.00
Continuous variables are expressed as mean ± SD; categorical variables are expressed as number (percentage
a
Thromboembolic events occurred during bridging anticoagulation
b
Bleeding events occurred during bridging anticoagulation
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40 Page 7 of 10

Fig. 2 Incidence of bleeding events during 4 weeks between three groups

Fig. 3 The secondary endpoints between three groups including (a) volume of drainage 4 days after surgery, (b) ICU length of stay, (c)
postoperative length of stay, (d) time of achieving target INR
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40
Fig. 4 Risk factors of bleeding events in patients after MHVR based on a multivariate analysis
patients suffered a thromboembolic stroke at 6 and 16
days after surgery, respectively, in the UFH group. Both
patients had atrial fibrillation and pulmonary hyperten-
sion, and one of whom had infective endocarditis and
history of embolism. Although the trial did not have
enough thromboembolic events to provide evidence of
treatment efficacy, the occurrence of thromboembolic
stroke demonstrates the necessity of bridging anticoagu-
lation and personalized management. The dose of war-
farin can be appropriately increased to prevent
thromboembolic events for patients with high-risk fac-
tors for embolism.
Our findings, in terms of bleeding event rates in differ-
ent bridging anticoagulation therapies following elective
MHVR, were similar to published studies. In previous
studies [7.9–12], the incidence of bleeding events in the
UFH group were 1.8 to 10%, and the incidence of bleed-
ing events in the LMWH group were 0.8 to 10%. Al-
though the rate of bleeding events in the LMWH group
(9.3%) was higher than that of the other two groups
(2.3% or 6.3%) in our study, no statistical difference was
found in the incidence of bleeding events during bridg-
ing anticoagulation. LMWH has a longer elimination
half-life compared to heparin [15] and vitamin K and
protamine sulfate are antagonists for warfarin and hep-
arin [16]. This means that using LMWH bridging antic-
oagulation is a huge challenge for postoperative bleeding
events.
Besides, compared with foreign cardiac surgery cen-
ters, the postoperative bridging anticoagulant dose (ei-
ther therapeutic or prophylactic) was lower in Chinese
cardiac surgery centers. In our study, the dose of UFH
(25 IU/kg per dose four times daily) is lower than the
prophylactic dose and the dose of LMWH (4000 IU of
anti-Xa per dose twice daily) is between the therapeutic
dose and the prophylactic dose used in foreign countries
[7, 8]. In 18 patients presented with bleeding events, 4
(22.2%) patients’ INRs were above the target range, and
Page 8 of 10
the INRs of other 14 (77.8%) were in the target range.
These can reflect the racial corporeity and high sensitiv-
ity of Chinese patients to anticoagulation. So a first pro-
spective cohort study was performed to assess different
bridging anticoagulation therapies used early after
MHVR in Chinese patients and provide Chinese evi-
dences for the development of related guidelines or
consensus.
Notably, mainly, the relevant data and medical costs
related to bridging therapy were collected, and these
data, in general, were not reported in previous studies.
The statistical test for significance indicated a shortening
trend, although significance is missed in ICU length of
stay (P = 0.08), postoperative length of stay (P = 0.08),
and time of achieving target INR (P = 0.06), which has
been reported in previous studies [11]. Despite 10 bleed-
ing events in the LMWH group, all bleeding events were
minor bleeding events, which can hardly delay the ICU
length of stay or increase volume of drainage. On the
other hand, previous studies [17] have shown that hep-
arin and LMWH appear to be a dose-dependent safe,
and effective anti-inflammatory agent. Compared with
the other two groups, the bridging anticoagulant dose in
the LMWH group was the highest, which may result in
a shortening trend in ICU length of stay. Additionally,
the reduced time of achieving target INR enables pa-
tients to benefit from the anticoagulation effect of war-
farin earlier, and the prior discharge can lower hospital
costs and medicine costs. Higher-level studies with lar-
ger sample sizes, longer follow-up, or randomized pros-
pected controlled trial are needed to explore whether
LMWH can shorten the ICU length of stay, postopera-
tive time, and time of achieving target INR.
Meanwhile, the creatinine level and hypertension were
identified as two bleeding risk factors through univariate
analysis. The two factors were included in the items of
HAS-BLED score, which was initially proposed to assess
the 1-year bleeding risk of patients with atrial fibrillation
Li et al. Journal of Cardiothoracic Surgery (2020) 15:40
and oral anticoagulation therapy [18]. This represents a
“real world” about bleeding risk factors after implant-
ation of a mechanical heart valve and can demonstrate
that close follow-up and personalized management were
required in patients with bleeding risk factors.
Limitations
Nonrandomization is the main limitation of the pro-
spective study. Posteriorly, lack of enough thrombo-
embolic events to evaluate the efficacy of bridging
anticoagulation, but the occurrence of permanent
thromboembolic stroke demonstrates the necessity of
bridging anticoagulation and personalized management.
Moreover the endpoint lacked an assessment for early
postoperative mortality, which was related to strict ex-
clusion criteria that precluded patients with critical peri-
operative states. Further studies with larger sample sizes,
longer follow-up or randomized prospected controlled
trial are needed to confirm our findings.
Conclusions
For Chinese patients, LMWH bridging anticoagulation
exists challenge of increasing the incidence of bleeding
events, but exists a trend that enables patients to benefit
from the anticoagulation effect earlier. Close follow-up
and personalized management are required in patients
with thromboembolic and bleeding risk factors.
Abbreviations
ACC/AHA: American College of Cardiology/American Heart Association;
ACCP: American College of Chest Physician; APTT: Activated partial
thromboplastin time; BMI: Body mass index; ICU: Intensive Care Unit;
INR: International normalized ratio; ISTH: International Society of Thrombosis
and Haemostasis; LDL: Low-density lipoprotein; LMWH: Low-molecular-
weight heparin; LVEF: Left ventricular ejection fraction; MHVR: Mechanical
heart valve replacement; NYHA: New York Heart Association;
UFH: Unfractionated heparin
Acknowledgements
We acknowledge technical and financial support by cardiovascular surgery
and department of Pharmacy, Lanzhou University First Affiliated Hospital.
Authors’ contributions
Xin-An Wu, Bing Song and Liang Qi participated in conception and design
of the study. Shi-Dong Liu, Wei Sun and Yuan-Min Li obtained and organized
the dataset. Shi-Dong Liu and Bo-Xia Li performed the statistical data ana-
lysis. Shi-Dong Liu, Bo-Xia Li and Shu-Sen Sun interpreted study data and
drafted the article. Bo-Xia Li completed the article revise. All authors provided
critical revisions of the article and approved the manuscript.
Funding
1. Science Foundation for Young Scientists of Gansu province (1506RJYA264);
2. Scientific Research Foundation of Clinical Pharmacy Branch of Chinese
Medical Association—Wu Jieping Medical Foundation (LCYX-Q030/
320.6750.19090–40).
3. Hospital Funds of First Hospital of Lanzhou University (ldyyyn2014–03,
ldyyyn2018–03).
Availability of data and materials
The dataset analyzed during the current study may be available from the
authors on reasonable request.
Page 9 of 10
Ethics approval and consent to participate
The ethics committee of the First Hospital of Lanzhou University approved
the study protocol and authorized its conduct and follow-up (LDYYLL2018–
154). Individual patient consent for inclusion in the study was obtained.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou
730000, China. 2First Clinical Medical College, Lanzhou University, Lanzhou
730000, China. 3Cardiovascular Surgery, First Hospital of Lanzhou University,
Lanzhou 730000, China. 4College of Pharmacy and Health Sciences, Western
New England University, Springfield, MA 01119, USA.
Received: 4 July 2019 Accepted: 17 February 2020
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